Molecular Cancer Therapeutics最新文献

{"title":"Vitamin A Metabolism and Resistance of Hepatic Metastases to Immunotherapy.","authors":"Peter C Jones, Daniel D Von Hoff","doi":"10.1158/1535-7163.MCT-24-0367","DOIUrl":"10.1158/1535-7163.MCT-24-0367","url":null,"abstract":"<p><p>The liver is an immune-tolerant organ, allowing for organ transplantation with less immune suppression compared with other organs. It also provides fertile soil for tumor metastases, which tend to be more resistant to checkpoint blockade immunotherapy than metastases in other organs. This resistance may result from the sum of incremental evolutionary adaptions in various cell types to prevent overaction to antigens absorbed from the gut into the portal circulation or it might involve a central mechanism. Here, we propose that metabolism of vitamin A, which is highly concentrated in the liver, is a root source of tolerance and resistance of hepatic metastases to checkpoint blockade. Suppression of retinoic acid synthesis from vitamin A with disulfiram may mitigate tolerance and produce enhanced immunotherapy treatment results for patients with liver metastases.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"345-353"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STAT5 Activation Enhances Adoptive Therapy Combined with Peptide Vaccination by Preventing PD-1 Inhibition.","authors":"Aaron E Fan, Hussein Sultan, Takumi Kumai, Valentyna I Fesenkova, Juan Wu, John D Klement, Joshua D Bernstock, Gregory K Friedman, Esteban Celis","doi":"10.1158/1535-7163.MCT-24-0505","DOIUrl":"10.1158/1535-7163.MCT-24-0505","url":null,"abstract":"<p><p>Adoptive cell therapy (ACT) using retrovirally transduced T cells represents a promising strategy for enhancing antitumor responses. When used with TriVax, a peptide vaccination strategy, this approach synergistically expands antigen-specific cell populations. STAT5 plays a vital role as a transcription factor in regulating T-cell proliferation and their differentiation into effector and memory T cells. We aimed to explore the combination therapy using CD8 T cells engineered to express constitutively active STAT5 (CA-STAT5) with vaccines. CD8 T cells were transduced with a retrovirus (RV) encoding the mouse gp100 T-cell receptor (TCR). In certain treatment groups, cells were also co-transduced with RV encoding CA-STAT5. We assessed transduction efficiency and functional activity through flow cytometry and various functional assays. B16F10 tumor-bearing mice were treated with ACT using RV-transduced CD8 T cells and subsequently vaccinated with TriVax. We demonstrate that TriVax selectively enhanced the expansion of ACT cell populations bearing gp100-specific TCRs. T cells engineered to express CA-STAT5 showed not only increased expansion and polyfunctionality but also reduced PD-1 expression, leading to decreased cellular exhaustion. In a B16F10 melanoma mouse model, our approach yielded a potent antitumor effect, with CA-STAT5 further amplifying this response. We found that CA-STAT5 improved antitumor activities, in part, by attenuating the PD-1/PD-L1 inhibitory pathway. These findings indicate that TCR-transduced CD8 T cells can undergo antigen-dependent expansion when exposed to TriVax. Additionally, the expression of CA-STAT5 enhances T-cell proliferation and persistence, partly by promoting resistance to PD-1/PD-L1-mediated inhibition in antitumor T cells.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"419-430"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Designed Anti-PD-L1/OX40 Bispecific Antibody Augments Both Peripheral and Tumor-Associated Immune Responses for Boosting Antitumor Immunity.","authors":"Baocun Li, Shiyong Gong, Nianying Zhang, Beilei Shi, Zhou Lv, Yu Zhang, Naren Gaowa, Liqin Dong, Danqing Wu, Jianfu Wu, Fan Liu, Rui Zhang, Ramin Behzadigohar, Vinod Ganju, Chengbin Wu, Xuan Wu","doi":"10.1158/1535-7163.MCT-24-0330","DOIUrl":"10.1158/1535-7163.MCT-24-0330","url":null,"abstract":"<p><p>Bispecific antibodies (BsAb) combining simultaneous PD-L1 blockade and conditional costimulatory receptor activation have been developed to improve immune checkpoint therapy response. However, several PD-L1-based BsAbs have encountered clinical challenges, including insufficient activity or unexpected toxicity. In this study, we propose OX40 as a more suitable target partner for PD-L1-based BsAb design compared with ongoing clinical partners (CD27 and 4-1BB). We present a novel Fc-silenced tetravalent PD-L1/OX40 BsAb (EMB-09), which efficiently blocks PD-1/PD-L1 interactions and induces PD-L1-dependent OX40 activation, leading to enhanced T-cell activation. EMB-09 demonstrated improved antitumor activity compared with the anti-PD-L1 mAb. Significantly, EMB-09 activated effector memory T cells in the peripheral immune system and promoted the influx of stem-like CD8+ T cells into the tumor site, resulting in a more active phenotype of CD8+ tumor-infiltrating lymphocytes. In an ongoing first-in-human study in patients with advanced refractory solid tumors (NCT05263180), EMB-09 demonstrated a consistent pharmacodynamic response and early efficacy signals.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"317-330"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOC2L promotes paclitaxel resistance in various types of ovarian cancers by decreasing NDUFA4 through histone acetylation suppression.","authors":"Hao Gu, Suwan Qi, Jiaying Chen, Hongqin Wu, Jianjuan Xu, Yaling Feng","doi":"10.1158/1535-7163.MCT-24-0512","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0512","url":null,"abstract":"<p><p>Ovarian cancer (OC) is a common malignant tumor in the female reproductive system. Paclitaxel resistance is the primary cause of treatment failure in patients with OC. Therefore, elucidating the mechanisms by which OC develops paclitaxel resistance is crucial for achieving better therapeutic outcomes. This study analyzed data from GSE50831 (the response of 21 OC cell lines to paclitaxel), GSE26193 (the progression of 107 patients with OC) datasets, and the Ovarian Cancer Genome Atlas (TCGA). Key differentially expressed genes were selected through intersection analysis, Least Absolute Shrinkage And Selection Operator (LASSO), and multivariate Cox regression analysis. Experiments were conducted to validate the candidate gene, NOC2L, and explore its role in the development of paclitaxel resistance in OC cells. Data from these datasets showed that NOC2L was upregulated in all OC cell lines after paclitaxel treatment, and this upregulation was associated with poorer patient progression. Both loss- and gain-of-function experiments confirmed that NOC2L promotes OC cell resistance to paclitaxel. The TCGA dataset showed that NOC2L is negatively correlated with the NADH:Ubiquinone oxidoreductase core subunit family (NDUF) proteins: NDUFB4, NDUFA1, NDUFS4, NDUFB1, NDUFA2, NDUFA4, and MT-ND3. Studies have revealed that NOC2L decreases the expression of NDUF proteins, particularly NDUFA4, via suppressing histone acetylation, resulting in a remodeling of energy metabolism towards aerobic glycolysis. Collectively, NOC2L inducing energy metabolism to aerobic glycolysis is a consistent mechanism in various OC cells resistant to paclitaxel. NOC2L, hence, is a promising target to improve the sensitivity of OC cells to paclitaxel.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Broad-Spectrum Efficacy of CEACAM6-Targeted Antibody-Drug Conjugate with BET Protein Degrader in Colorectal, Lung, and Breast Cancer Mouse Models.","authors":"Hiroyuki Kogai, Shuntaro Tsukamoto, Minaho Koga, Masayuki Miyano, Tsuyoshi Akagi, Atsumi Yamaguchi, Kiyoshi Mori, Kunihito Gotoh, Youya Nakazawa","doi":"10.1158/1535-7163.MCT-24-0444","DOIUrl":"10.1158/1535-7163.MCT-24-0444","url":null,"abstract":"<p><p>Despite remarkable advances in cancer treatment, most solid cancers remain difficult to cure. We recently developed an antibody-drug conjugate (ADC; 84-EBET) for pancreatic cancer by using the carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) antibody #84.7 and the bromodomain and extra-terminal (BET) protein degrader EBET. In this study, we showed the overexpression of CEACAM6 in colorectal, lung, and breast cancers and the broad-spectrum efficacy of 84-EBET in mouse models of these cancers. In vitro assays using cancer organoids and cell lines of colorectal, lung, and breast cancers revealed that 84-EBET was more potent than ADCs with known approved payloads-DXd, SN38, and monomethyl auristatin E-or standard chemotherapies. In mouse studies, a single injection of 84-EBET induced marked regression of colorectal-, lung-, and breast cancer patient-derived xenograft tumors and cell line-derived xenograft tumors. Moreover, in mouse syngeneic colorectal cancer, lung cancer, and breast cancer models resistant to PD-1 antibody, the combination of 84-EBET and PD-1 antibody induced complete regression of most tumors. Mechanistically, 84-EBET degraded bromodomain-containing protein 4 in both cancer and stromal cells via bystander efficacy. It decreased stromal inflammatory phenotypes and increased activated T-cell numbers in tumors. These results demonstrate that delivering BET protein degraders to tumors and their microenvironments via a CEACAM6-targeted ADC may be effective against a wide range of solid cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"392-405"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of PSF Activity Overcomes Resistance to Treatment in Cancers Harboring Mutant p53.","authors":"Ken-Ichi Takayama, Tomohiro Sato, Teruki Honma, Minoru Yoshida, Satoshi Inoue","doi":"10.1158/1535-7163.MCT-24-0418","DOIUrl":"10.1158/1535-7163.MCT-24-0418","url":null,"abstract":"<p><p>Mutations in the TP53 tumor suppressor genes are prevalent in aggressive cancers. Pharmacologic reactivation of dysfunctional p53 due to mutations is a promising strategy for treating such cancers. Recently, a multifunctional proline- and glutamine-rich protein, polypyrimidine tract-binding protein-associated splicing factor (PSF), was identified as a key driver of aggressive cancers. PSF promotes the expression of numerous oncogenes by modulating epigenetic and splicing mechanisms. We previously screened a small-molecule library and discovered compound No. 10-3 as a potent PSF inhibitor. Here, we report the discovery of a No. 10-3 analog, 7,8-dimethoxy-4-(4-methoxy-phenyl)-chromen-2-one (C-30), as a potent PSF inhibitor. Compared with No. 10-3, C-30 treatment specifically suppressed the growth and induced apoptosis of mutant p53-bearing and therapy-resistant cancer cells. Interestingly, C-30 activated a set of p53-regulated genes in therapy-resistant cancer cells. A comprehensive analysis of PSF and p53-binding regions demonstrated a higher level of PSF-binding potential in mutant p53-expressing cancer cells around genomic regions identified as p53-binding peaks in p53 wild-type cancer cells. Treatment of mutant p53-expressing cancer cells with C-30 decreases PSF binding around these sites, leading to activated histone acetylation. We further demonstrated that C-30 impaired tumor growth and increased the expression of p53 target genes in vivo. These results suggested that C-30 produces tumor-suppressive effects similar to the functional reactivation of p53, providing a rationale for the inhibition of PSF activity as a promising therapy against treatment-resistant cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"370-383"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A B7-H3-Targeted CD28 Bispecific Antibody Enhances the Activity of Anti-PD-1 and CD3 T-cell Engager Immunotherapies.","authors":"Gregory L Moore, Veronica G Zeng, Juan E Diaz, Christine Bonzon, Kendra N Avery, Rumana Rashid, Jing Qi, Dong Hyun Nam, Jonathan Jacinto, Matthew A Dragovich, Yoon Kyung Kim, Karen P Balcazar, Charles G Bakhit, Araz Eivazi, Hanh Nguyen, Umesh S Muchhal, David E Szymkowski, John R Desjarlais, Michael Hedvat","doi":"10.1158/1535-7163.MCT-24-0327","DOIUrl":"10.1158/1535-7163.MCT-24-0327","url":null,"abstract":"<p><p>T-cell activation is a multistep process requiring T-cell receptor engagement by peptide-MHC complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell-mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells and cancer cells and in mice engrafted with human peripheral blood mononuclear cells and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated IL2 and IFNγ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the antiapoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell-mediated cytotoxicity in vitro. XmAb808 combined with an EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Furthermore, XmAb808 combined with an anti-programmed cell death protein 1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti-programmed cell death protein 1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen-targeted anti-CD3 (Signal 1) T-cell engagers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"331-344"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation of an Anchored Immunotherapy Strategy with Aluminum Hydroxide-Tethered IL-12 in Dogs with Advanced Malignant Melanoma.","authors":"Matheus Moreno Passos Barbosa, Rebecca L Kamerer, Joanna Schmit, Angel J Lopez, Rachel Uyehara, Robert Tighe, Sailaja Battula, Howard L Kaufman, Timothy M Fan","doi":"10.1158/1535-7163.MCT-24-0317","DOIUrl":"10.1158/1535-7163.MCT-24-0317","url":null,"abstract":"<p><p>Melanoma is an aggressive cancer in dogs involving skin and mucosa similar to humans. Anchored immunotherapeutics offer a novel approach to increase intratumoral retention of therapeutic payloads while decreasing systemic exposure, and this strategy can be critically evaluated through a comparative oncology approach. JEN-101 is an anchored canine IL-12 tethered to aluminum hydroxide administered by local injection. A phase I study was conducted to determine the tolerability, activity, and immune responses of JEN-101 in dogs with advanced melanoma. A 3 + 3 dose-escalation design was used to evaluate intratumoral injection of JEN-101 at 1, 3, 10, or 20 μg/kg every 3 weeks for four cycles. A second course was allowable in the absence of disease progression or toxicity. Peripheral blood, serum, and tumor biopsies were collected at baseline and at prespecified timepoints for pharmacokinetic and immune analyses, which included serum cytokine assay, IHC, and gene expression assessment. JEN-101 was well tolerated with adverse events being fever, lethargy, and isolated elevated liver enzymes. Five dogs experienced grade 3 events, and no grade 4 events were observed. Pharmacokinetic analysis showed a trend toward dose-related maximum serum concentration within 8 hours of injection. Responding dogs demonstrated increased systemic IFN-γ and IL-10 AUC levels and local recruitment of CD3+ T cells. Increased proinflammatory and antigen-processing gene expression was identified in responding lesions. JEN-101 was well tolerated with evidence of biological and therapeutic activities. Anchored IL-12 immunotherapy merits further investigation in dogs with melanoma, and our approach represents an immunocompetent model to inform human clinical trials.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"406-418"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking Feedback Immunosuppression of Antigen Presentation in Brain Tumor During Oncolytic Virotherapy with oHSV-mshPKR.","authors":"Nobushige Tsuboi, Kimberly A Rivera-Caraballo, Upasana Sahu, Rafal Pacholczyk, Eugene Douglass, Theodore S Johnson, Qin Wang, Ravindra Kolhe, Catherine C Hedrick, David H Munn, Bangxing Hong","doi":"10.1158/1535-7163.MCT-24-0629","DOIUrl":"10.1158/1535-7163.MCT-24-0629","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most frequent malignant brain tumor. We recently discovered that oncolytic herpes simplex virus engineered to disable tumor-intrinsic protein kinase R (PKR) signaling (oHSV-shPKR) could increase oHSV oncolysis and antitumor immune response. However, in this study, we show that disabling tumor-intrinsic PKR signaling can also induce the activation of the indoleamine 2,3-dioxygenase (IDO) signaling pathway. Both GBM tumor progression and oHSV intratumoral therapy increased infiltration of IDO+CD11c+ dendritic cells (DC) into the tumor. The coculture of oHSV-infected human GBM neurospheres with monocyte-derived DCs (MoDC) dramatically increased IDO signaling activation in MoDCs through type-I IFN signaling. Addition of IDO inhibitor (indoximod) in the coculture significantly increased MoDC activation and reduced the consumption of tryptophan. Combining indoximod and oHSV significantly inhibited tumor growth and induced antigen-specific CD8+ T-cell activation. These results suggest that inhibition of the IDO pathway could significantly block feedback immunosuppression during oncolytic virotherapy of GBM.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"444-452"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCL12-Targeted Immunomodulatory Gene Therapy Reduces Radiation-Induced Fibrosis in Healthy Tissues.","authors":"James T Paget, Joseph A Ward, Andrew R McKean, David C Mansfield, Martin McLaughlin, Joan N Kyula-Currie, Henry G Smith, Victoria Roulstone, Chunhei Li, You Zhou, Thomas Hardiman, Anita Grigoriadis, Devin O'Brien Coon, Sheeba Irshad, Alan A Melcher, Kevin J Harrington, Aadil Khan","doi":"10.1158/1535-7163.MCT-23-0872","DOIUrl":"10.1158/1535-7163.MCT-23-0872","url":null,"abstract":"<p><p>Radiation-induced fibrosis (RIF) is a progressive pathology deleteriously impacting cancer survivorship. CXCL12 is an immune-stromal signal implicated in fibrosis and innate response. We hypothesized that modulation of CXCL12 would phenotypically mitigate RIF. CXCL12 expression was characterized in a rodent model of RIF and its expression modulated by the intravascular delivery of lentiviral vectors encoding small hairpin RNA to silence (LVShCXCL12) or overexpress (LVOeCXCL12) CXCL12. Multimodal fibrotic outcomes were quantified, and flow cytometry and Y-chromosome lineage-tracking studies performed to examine cellular recruitment and activation after radiotherapy. Whole-tissue RNA sequencing was used to examine matrisomal response. MATBIII tumors were engrafted within tissues with differing levels of CXCL12 expression, and tumoral response to RT was evaluated. CXCL12 was upregulated in irradiated fibroblasts demonstrating DNA damage after radiotherapy, which led to the recruitment of CD68+ macrophages. Silencing CXCL12 with LVShCXCL12 demonstrated reduced RIF phenotype as a result of decreased macrophage recruitment. Transcriptomic profiling identified osteopontin (OPN; SPP1) as being highly differentially expressed in LVShCXCL12-treated tissues. Tumors growing in tissues devoid of CXCL12 expression responded better after RT because of reductions in peritumoral fibrosis as a result of decreased CXCL12 and OPN expression at the tumor/normal tissue interface. This was also associated with greater CD8+ T-cell infiltration in tumors with less fibrosis. Antibody-mediated OPN blockade slowed tumor growth by increased intratumoral CD8+ T-cell activation. The CXCL12/OPN axis is an important node of immune/matrisomal cross-talk in the development of fibrosis. Therapeutic manipulation of this axis may offer greater antitumor efficacy while also reducing adverse effects.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"431-443"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}